Water envelope has a critical impact on the design of protein–protein interaction inhibitors

Abstract

We show that a water envelope network plays a critical role in protein–protein interactions (PPI).

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

“…Instead, we identied displacement of a conserved, energetically unfavorable and unusually solvent-exposed water molecule as the major origin for the enhanced affinity. Water displacement or replacement strategies have been used for ligand optimization before [36][37][38][39][40] and are especially effective for buried water molecules. However, the role of exposed solvent shell wateralthough clearly important for bindingis still poorly understood, 29,30,41 and the manipulation of water molecules that predominantly face the solvent have been rarely used for ligand optimization.…”

Can Quantum Chemistry Improve the understanding of Protein-Ligand Interactions? Implications for Structure Based Drug Discovery

“…We chose complexes of PEX14 with inhibitors -5L87, 5L8A, 5N8V, 5OML, 6RT2, 6SPT -and with peptides -2W84, 2W85, and 4BXU. 23,[35][36][37][38][39][40][41][42][43][44][45][46] A modified variant of 2W84 was prepared, where a key aspartate is converted into a glycine (2W84').…”

“…B) Summary of SAR data on several PEX14 inhibitors collected from the literature, the Kds are in nM. 23,[35][36][37][38][39][40][41] C) Part of PEX14 structure with a small peptide, 2W84, 42,43 showing the target protein-protein interface. The blue ribbon and atoms are the small peptide (up), while the brown ribbon and atoms represent PEX14 (down).…”

Elucidation of a Thermodynamical Feature Attributed to Substrate Binding to the Prokaryotic H+/Oligopeptide Cotransporter YdgR with Calorimetric Analysis: The Substrate Binding Driven by the Change in Entropy Implies the Release of Bound Water Molecules from the Binding Pocket

“…The water molecules in the binding pocket of YdgR were predicted using the “Solvent Analysis” module based on the three-dimensional reference interaction site model (3D-RISM) theory in MOE. − The template YdgR apo -structure (PDB, 6GS1) with hydrogen added by MOE and the docking YdgR structures with dipeptide were used to predict water molecules in the binding pocket. The calculation parameters used were as follows: the dimension of the grid spacing was 0.35 Å, a distance of 7 Å was set for the boundary box where atoms are extended, the convergence or precision of 3D-RISM was set to “tight”, and the NDIIS (the Number of copies of Direct Inversion in the Iterative Subspace) was set to 5.…”